Blood clotting is a process of control of the blood stream essential for the survival of mammals. The process of clotting and the subsequent dissolution of the clot after wound healing has taken place, after vascular damage and can be divided into four phases:                1. The phase of the initiation of the coagulation cascade either after vessels injury or vasoconstriction leads to low amount of thrombin generation;        2. The next phase is the amplification phase where platelets are activated by thrombin. The platelets attach to the site of the vessel wall damage and form a platelet aggregate which is crosslinked by fibrinogen (fibrin). At the meantime, the complexes of clotting factors (tenase and prothrombinase) can form of the surface of activated platelets. The platelets accelerate blood clotting by means of this mechanism;        3. The formation of the thrombus is stabilized by the fibrin network which is formed consecutive to the cleavage of fibrinogen by the large amount of thrombin;        4. After wound healing, the thrombus is dissolved by the action of the key enzyme of the endogenous fibrinolysis system, plasmin.        
In a more detailed scenario, the initiation phase can be driven by two alternative pathways: the intrinsic and the extrinsic pathway. These pathways are initiated by different mechanisms, but in the later phase they converge to give a common final path of the clotting cascade starting with the activation of clotting factor X. The activated factor X is responsible for the formation of thrombin from the inactive precursor prothrombin circulating in the blood. The formation of a thrombus on the bottom of a vessel wall abnormality without a wound is commonly described as the result of the intrinsic pathway. Whereas, fibrin clots formation as a response to tissue damage or an injury is the result of the extrinsic pathway. Both pathways comprise a relatively large number of proteins, which are known as clotting factors.
The “extrinsic” pathway is so called because an exogenous agent (i.e., TF) is required for activation of the clotting factors in plasma. The TF:FVIIa complex is the key initiator of the coagulation protease cascade and activates both FIX to FIXa and FX to FXa.
Alternatively, the “intrinsic” pathway is initiated when prekallikrein, high molecular weight kininogen, factor XI and XII bind to a negatively charged surface: it is the contact phase. The result of these processes is the activation of prekallikrein, factor XII, and finally factor XI that leads, in the presence of Ca2+ ions, to the activation of factor IX.
Whatever the initiating pathway, the generation of factor IXa and factor Xa leads to the formation of low amounts of thrombin, which are able to activate the platelets through the cleavage of protease activated receptors and finally the cofactors factor V and factor VIII: it is the start of the amplification phase. Platelet activation plays a major role in the coagulation since it allows the formation of the two complexes which support the amplification phase: the tenase and the prothrombinase complexes. The tenase complex (FVIIIa:FIXa) plays a key role in amplifying the clotting cascade by activating factor X to factor Xa. The prothrombinase complex (FVa:FXa) activates prothrombin to thrombin, which is the central protease of the clotting cascade. Thrombin cleaves fibrinogen into unsoluble fibrin monomers that polymerize. Thrombin also activates the transglutaminase FXIII to FXIIIa that in turn cross-links soluble fibrin monomers into a fibrin matrix that leads to clot stabilization. Finally, the coagulation cascade is regulated by several natural anticoagulants (TFPI, Antithrombin, HCII, Prot C, Prot S . . . ).
Both clotting factor IX and factor X can be activated by means of the intrinsic pathway and the extrinsic pathway. Their activation are thus a central point of intersection between the two pathways of blood clotting. Moreover the activity of factor IXa is intimately linked to the presence of platelet since, after activation, platelets promote tenase complex formation that increases factor IXa activity by a fold of 200 000 (van Dieijen et al, J. Biol. Chem. 1981; 256: 3433-3442), giving it a central role in the rate limiting step of thrombin generation. Given its central role and its interdependency to platelets, we do know that factor IXa has an important role in both venous and arterial thrombosis.
Evidence is given by the fact that defects in factor IXa lead to hemophilia B. More precisely, the clinical phenotype of hemophilia B depends on the plasma FIX level. Thus, spontaneous bleeding occurs in patients with severe hemophilia (<1% FIX activity). Whereas mild FIX deficiency may not require prophylaxis to prevent bleeding during minor procedures, but interestingly, in epidemiological studies it has been associated with fewer cardiovascular events ({hacek over (S)}rárnek A et al, Lancet. 2003; 362: 351-354; Tuinenburg A el al, J Thromb Haemost. 2009; 7: 247-254). In mirror, increased concentrations of factor IXa in the blood lead to a significantly increased risk of thrombosis formation (Weltermann A, et al., J Thromb Haemost. 2003; 1: 28-32). And finally the regulation of factor IXa activity can reduce thrombus formation in animal models (Feuerstein G Z, et al., Thromb Haemost. 1999; 82: 1443-1445).
In conclusion, as described by Eikelboom in his recent review (Arterioscler Thromb Vasc Biol. 2010; 30: 382-7), “the narrow window for clinically important bleeding with a wider window for reduced cardiovascular events in hemophilia B carriers lends further support for FIXa as an attractive target for anticoagulant therapy.”
Numerous documents describe compounds with antithrombotic activity.
For instance, the U.S. Pat. No. 6,432,955 B1 is directed to anti-thrombotic compounds all comprising the following core:
which may be linked to a variety of side-chains.
Another example is the U.S. Pat. No. 6,602,864 B1 describing factor Xa inhibitors of formula:
where Z is an alkylenyl group.
The compounds of the formula I according to the invention are suitable for prophylactic and for therapeutic administration to humans who suffer from diseases which accompany thromboses, embolisms, hypercoagulability or fibrotic changes. They can be employed for secondary prevention and are suitable both for acute and for long-term therapy.
The invention therefore relates to a compound corresponding to the formula (I):
                in which:        R1 represents a hydrogen atom, a (C1-C6)alkyl group, a (C3-C7)cycloalkyl group, a (C3-C7)cycloalkyl-(C1-C6)alkyl- group, a Rb—O—Ra— group where Rb represents a (C1-C6)alkyl group or a (C3-C7)cycloalkyl group and Ra represents a (C1-C6)alkyl group, or a Rd-O—C(O)—O-Rc- group where Rd represents a (C1-C6)alkyl group or a (C3-C7)cycloalkyl group and Rc represents a (C1-C6)alkyl group, or a Rf—C(O)—O—Re— group where Re represents a (C1-C6)alkyl group and Rf represents a (C1-C6)alkyl group,        R2 represents a halogen atom, —OH, —CN, or a (C1-C6)alkyl group, or an —O—(C1-C6)alkyl group, said alkyl groups being non-substituted or substituted by one or more halogen atoms, identical to or different from one another, or a Rg-O—Rh—O— group where Rg represents a (C1-C6)alkyl group and Rh represents a (C1-C6)alkyl group,        R2′ represents a hydrogen atom or a (C1-C6)alkyl group,        R3 represents:        
                R4 and R5 represent, independently of one another, a (C1-C6) alkyl group or a (C3-C7)cycloalkyl group,        or R4 and R5 together form, with the nitrogen atom to which they are attached, a 3 to 7 membered heterocycloalkyl group comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen and sulphur, said heterocycloalkyl group being non-substituted or substituted by one or more groups, identical or different from one another, chosen from halogen atom and (C1-C6)alkyl group, (C1-C6)alkoxy group, —CF3, —OCF3,        R6 represents a halogen atom, a hydrogen atom, a (C1-C6)alkyl group, a (C1-C6)alkoxy group or —CN.        
The compounds of formula (I) comprise at least two asymmetric carbon atoms, identified by the asterisks (*1 and *2) in the formula below. They can thus exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, and their mixtures, including racemic mixtures, come within the invention.

The asymmetric carbon identified by the asterisk *1 in the above formula advantageously exhibits the (R) configuration. The asymmetric carbon identified by the asterisk *2 in the above formula advantageously exhibits the (S) configuration.
The compounds of formula (I) can exist in the form of bases or of addition salts with acids or bases. Such addition salts come within the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids or bases but the salts of other acids or bases, for example of use in the purification or isolation of the compounds of formula (I), also come within the invention.
In the context of the present invention:                a halogen atom is understood to mean a fluorine, chlorine, a bromine or an iodine;        a (C1-C6)alkyl group is understood to mean a saturated aliphatic group which comprises from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) and which is linear or branched. Mention may be made, by way of examples, of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like;        a (C3-C7)cycloalkyl group is understood to mean a cyclic alkyl group comprising between 3 and 7 carbon atoms, all the carbon atoms being involved in the cyclic structure. Mention may be made, by way of examples, of the cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups, and the like;        a heterocycloalkyl group is understood to mean a cycloalkyl group as defined above additionally comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen and sulphur. Mention may be made, by way of examples, of the azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl groups. This heterocycloalkyl group can be substituted, in any position, by one or more (for example by 1 to 3) groups, identical to or different from one another, chosen from halogen atoms and alkyl groups, alcoxy groups, —CF3, —OCF3;        a cycloalkyl-alkyl group is understood to mean a cyclic alkyl group as defined above and linked to an alkyl group as defined above. Mention may be made, by way of examples, of the cyclopropyl-methyl group, cyclopropyl-ethyl group and cyclobutyl-methyl group;        an alkoxy group is understood to mean an —O-alkyl radical where the alkyl group is as defined above;        an alkoxyalkyl group is understood to mean a radical of formula alkyl-O-alkyl, where the alkyl groups, which are identical to or different from one another, are as defined above.        
According to the present invention, the following stand out:                the compounds of Formula (IA) in which in formula R3 represents:        
or                the compounds of Formula (IB) in which R3 represents:        
and/or                the compounds of formula (I), (IA) or (IB) in which R2 represents a —OCF3 group,the other substituents being as defined for the compounds of Formula (I).        
In the formula (I), (IA), (IB), the following in particular stand out, or any of their combination:                R1 represents a hydrogen atom, a (C1-C6)alkyl group, a (C3-C7)cycloalkyl group, a (C3-C7)cycloalkyl-(C1-C6)alkyl group, a Rb—O—Ra— group where Rb represents a (C1-C6)alkyl group and Ra represents a (C1-C6)alkyl group, or a Rd-O—C(O)—O-Rc- where Rd represents a (C1-C6)alkyl group or a (C3-C7)cycloalkyl group and Rc represents a (C1-C6)alkyl group, or a Rf—C(O)—O—Re— where Re represents a (C1-C6)alkyl group and Rf represents a (C1-C6)alkyl group, and/or        R2 represents an halogen atom, —OH, —CN, or a (C1-C6)alkyl group, or a —O—(C1-C6)alkyl group, said alkyl groups being non-substituted or substituted by one or more halogen atom, identical to or different from one another, or a Rg-O—Rh—O— group where Rg represents a (C1-C6)alkyl group and Rh represents a (C1-C6)alkyl group, and/or        R2′ represents a hydrogen atom or a (C1-C6)alkyl group, and/or        R3 represents:        
                 and/or        R4 and R5 represent, independently of one another, a (C1-C6) alkyl group or a (C3-C7)cycloalkyl group, and/or        or R4 and R5 together form, with the nitrogen atom to which they are attached, a 3 to 7 membered N-heterocycloalkyl group comprising from 1 to 2 heteroatoms chosen from nitrogen, oxygen and sulphur, said heterocycloalkyl group being non-substituted or substituted by one or more halogen atoms, and/or        R6 represents a halogen atom, a hydrogen atom, a (C1-C6)alkyl group.        
According to the present invention, preference is given to the compounds of formula (I) in which:                R1 represents a hydrogen atom, a methyl, an ethyl, a propyl, an isopropyl, a butyl, an isobutyl, a cyclopentyl, a cyclopropylmethyl, a cyclobutylmethyl, a 2-methoxyethyl, a cyclohexyloxycarbonyloxymethyl, a 1-cyclohexyloxycarbonyl oxymethyl, a 2,2-dimethylpropionyloxymethyl,        R2 represents a chlorine atom, a fluorine atom, —OH, —CN, a methyl, an ethyl, a methoxy, an ethoxy, —CF3, —OCF3, a 2-methoxyethoxy,        R2′ represents a hydrogen atom, a methyl,        R3 represents:        
                R4 and R5 represent, independently of one another, a methyl or a cyclobutyl,        or R4 and R5 together form, with the nitrogen atom to which they are attached, a heterocycloalkyl group chosen from azetidin-1-yl or pyrrolidin-1-yl, said heterocycloalkyl group being non-substituted or substituted by one or two fluorine atoms,        R6 represents a hydrogen atom, a chlorine atom, a methyl.        
According to the present invention, preference is particularly given to the compounds of formula (I) in which:                R1 represents a hydrogen atom or a methyl,        R2 represents a chlorine atom, —CF3, —OCF3,        R2′ represents a hydrogen atom,        R3 represents:        
                R4 and R5 represent, independently of one another, a methyl,        or R4 and R5 together form, with the nitrogen atom to which they are attached, a heterocycloalkyl group chosen from azetidin-1-yl or pyrrolidin-1-yl, said heterocycloalkyl group being non-substituted or substituted by one or two fluorine atoms,        R6 represents a hydrogen atom.        
Among the compounds according to the invention, mention may in particular be made of the compounds hereinafter:
TABLE IIC 50IC50IUPAC Name generated from(μM)(μM)AutoNom ® (MDL, Elsevier)Chemical StructureIXaXa1(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.14.68 2(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl ester>5>5 3(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester>5ND 4(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.17ND 5(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl esterNDND 6(R)-3-(1-Amino-5-fluoro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.160.20 7(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.112 8(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid isobutyl ester1.600.10 9(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid cyclopropylmethyl ester0.760.029 10(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid cyclobutylmethyl ester1.300.086 11(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid isopropyl ester1.600.021 12 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid cyclopentyl ester1.500.043 13(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester1.600.021 14(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.110.004 15 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid cyclopropylmethyl ester0.780.12 16 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester1.300.074 17 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.0700.017 18(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid ethyl ester2.500.12 19 (R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid cyclopropylmethyl ester1.101 20(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid isopropyl ester1.500.63 21(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-{(S)-3-[2-((R)- 3-fluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.140.008 22(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.150.073 23(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid ethyl ester>51.60 24(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.140.002 25(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester1.100.097 26(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo pyrrolidin-1-yl]-propionic acid0.120.10 27(R)-3-(1-Amino-7-methoxy- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo pyrrolidin-1-yl]-propionic acid ethyl esterNDND 28(R)-3-(1-Amino-7-methyl- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.150.034 29(R)-3-(1-Amino-7-methyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.190.15 30(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.150.012 31(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester2.90ND 32(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.180.048 33(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester>5ND 34(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acidND0.032 35(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl esterNDND 36(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.150.47 37(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (6-pyrrolidin-1-yl-pyridine-3- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl esterNDND 38(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acidNDND 39(R)-3-(1-Amino-7-ethyl- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid ethyl esterNDND 40(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.100.022 41(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.120.047 42(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.121.20 43(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester0.530.060 44(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.120.014 45(R)-3-(1-Amino-7-ethoxy- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.160.067 46(R)-3-(1-Amino-7-ethoxy- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.130.0084 47(R)-3-(1-Amino-7-ethoxy- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.160.19 48(R)-3-(1-Amino-7-hydroxy- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acidND0.0064 49(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-{(S)-3-[2- (cyclobutyl-methyl-amino)- thiazole-5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.130.27 50(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.160.005 51(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester1.530.24 52(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl ester2.080.41 53(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.0840.027 54(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid methyl ester1.091.12 55(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid methyl ester0.556.12 56(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid0.0760.56 57(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester2.641.97 58(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.140.035 59(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester2.051.09 60(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.130.034 61(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester5.600.47 62(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.0920.016 63(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.110.042 64(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester0.620.40 65(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid methyl ester3.685.50 66(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-{(S)-3-[2-(3,3- difluoro-pyrrolidin-1-yl)-thiazole- 5-sulfonylamino]-2-oxo- pyrrolidin-1-yl}-propionic acid0.110.19 67(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester0.673.85 (Imax 73%) 68(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.291.91 (Imax 81%) 69(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester>23.85 (Imax 73%) 70(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(5- chloro-6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.270.59 71(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester>2ND 72(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino-5- methyl-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester>25.45 (Imax 71%) 73(R)-3-(1-Amino-7-fluoro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.352.77 (Imax 80%) 74(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(6-dimethylamino-5- methyl-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.100.81 75(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester>2ND 76(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(6- dimethylamino-5-methyl- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.230.65 77(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester0.750.11 78(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester1.890.80 79(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-dimethylamino- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.0700.033 80(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-2-oxo-3-(2-pyrrolidin-1-yl- thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid methyl ester2.32, Imax 64%3.23, Imax  63% 81(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-2-oxo-3-(2-pyrrolidin-1-yl- thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid0.0860.37 82(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester2.42, Imax 59%2.43, Imax 69% 83(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(6-dimethylamino- pyridine-3-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.0690.24 84(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid ethyl ester3.59, Imax = 60%0.94 85(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- azetidin-1-yl-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester3.32, Imax = 63% 0.78 86(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(5-chloro-6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid methyl ester3.1, Imax 50%2.84, Imax 43%  87(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-3-(5-chloro-6- dimethylamino-pyridine-3- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.111.65, Imax 85% 88(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid methyl ester4.30, Imax 46%3.08, Imax 58% 89(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-[(S)-3-(2-azetidin-1-yl- thiazole-5-sulfonylamino)-2-oxo- pyrrolidin-1-yl]-propionic acid0.190.56 90(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid methyl ester2.05, Imax = 41%ND 91(R)-3-(1-Amino-7- trifluoromethyl-isoquinolin-6-yl)- 2-{(S)-3-[2-(3,3-difluoro- pyrrolidin-1-yl)-thiazole-5- sulfonylamino]-2-oxo-pyrrolidin- 1-yl}-propionic acid0.122.18, Imax = 68% 92(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-3-(2- azetidin-1-yl-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.120.019 93(R)-3-(1-Amino-7-chloro- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid butyl ester2.112, Imax = 63%1.0 94(R)-3-(1-Amino-7-cyano- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl ester2.56, Imax = 58%1.06 95(R)-3-(1-Amino-7-cyano- isoquinolin-6-yl)-2-[(S)-2-oxo-3- (2-pyrrolidin-1-yl-thiazole-5- sulfonylamino)-pyrrolidin-1-yl]- propionic acid0.0800.025 96(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid0.0830.042 97(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid ethyl esterNDND 98(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid propyl esterNDND 99(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid cyclopropylmethyl esterNDND 100(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid butyl esterNDND 101(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid isopropyl esterNDND 102(R)-3-[1-Amino-7-(2-methoxy- ethoxy)-isoquinolin-6-yl]-2-[(S)- 3-(2-dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid ethyl ester3.800.037 103(R)-3-[1-Amino-7-(2-methoxy- ethoxy)-isoquinolin-6-yl]-2-[(S)- 3-(2-dimethylamino-thiazole-5- sulfonylamino)-2-oxo-pyrrolidin- 1-yl]-propionic acid0.170.0014 104(R)-3-(1-Amino-5-fluoro-3- methyl-isoquinolin-6-yl)-2-[(S)-2- oxo-3-(6-pyrrolidin-1-yl-pyridine- 3-sulfonylamino)-pyrrolidin-1-yl]- propionic acidNDND 105(R)-3-(1-Amino-5-fluoro-3- methyl-isoquinolin-6-yl)-2-[(S)-2- oxo-3-(6-pyrrolidin-1-yl-pyridine- 3-sulfonylamino)-pyrrolidin-1-yl]- propionic acid methyl esterNDND 106(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid 2- methoxy-ethyl esterNDND 107(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid 2,2-dimethyl-propionyloxymethyl esterNDND 108(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid 1- cyclohexyloxycarbonyloxy-ethyl esterNDND 109(R)-3-(1-Amino-7- trifluoromethoxy-isoquinolin-6- yl)-2-[(S)-2-oxo-3-(2-pyrrolidin- 1-yl-thiazole-5-sulfonylamino)- pyrrolidin-1-yl]-propionic acid cyclohexyloxycarbonyloxymethyl esterNDND 110(2R)-3-[1-amino-7- (trifluoromethoxy)isoquinolin-6- yl]-2-[(3S)-2-oxo-3-{[(2- pyrrolidin-1-yl-1,3-thiazol-5- yl)sulfonyl]amino}pyrrolidin-1- yl]propionic acid methoxymethyl esterNDNDas well as their enantiomers, diastereoisomers and their mixtures, and the pharmaceutically acceptable salts thereof.
According to a further object, the present invention concerns the process of preparation of the compounds of formula (I) of the invention.
In that which follows, Pg, Pg1 and Pg2 are protective groups. Said protective groups are to be understood to mean a group which makes it possible, on the one hand, to protect a reactive functional group, such as a hydroxyl or an amine, during a synthesis and, on the other hand, to regenerate the reactive functional group intact at the end of the synthesis. Examples of protective groups and also of methods for protection and deprotection are given in “Protective Groups in Organic Synthesis”, Green et al., 4th Edition (John Wiley & Sons Inc., New York), 2007.
In accordance with the invention, the compounds of general formula (I) can be prepared according to the process presented in Scheme 1.
In Scheme 1, an aminopyrrolidinone is used as starting material.

The process of the invention of the preparation of a compound of formula (I) may comprise the step of reacting a compound of formula (D):
with a compound of formula R3—SO2-Hal,where R1 is H, alkyl, cycloalkyl or cycloalkylalkyl-, R2, R2′ and R3 are defined as in formula (I) and X represents either H or Pg2, where Pg2 is an amino protective group such as triphenylmethyl (trityl) and Hal is a halogen atom, preferably Cl;optionally followed by:                deprotection of Pg2, where X represents Pg2; and/or        optional hydrolysis of R1 in order to obtain the corresponding compound of formula (I) with R1 being H, this hydrolysis being optionally followed by an esterification with the corresponding R1-Hal where Hal is a halogen atom such as Cl, to obtain the corresponding compounds of formula (I) with alternative R1; or        optional transesterification of R1 with the corresponding R1—OH, in the presence of an alkoxide.        
The above esterification may be appropriate in particular to obtain compounds of formula (I) with R1 is Rb—O—Ra—, Rd-O—C(O)—O-Rc- or Rf—C(O)—O—Re—.
The process of the invention may also comprise the further step of isolating the desired compound.
Particular embodiments of the process of the invention are described below.
Particular Embodiment for Step 1a.
The aminopyrrolidinone, for example the (S)-aminopyrrolidinone, the primary amine functional group of which is protected by a group Pg1 (such as a tert-butyl or benzyl carbamate), can be condensed with an alkylpropiolate, a cycloalkylpropiolate or a cycloalkylalkyl-propiolate in order to result in the 2-pyrrolidinoacrylate of structure A, in which R1 represents an alkyl, a cycloalkyl or a cycloalkylalkyl- group (contributed by the alkyl-, cycloalkyl- or cylcoalkylalkyl-propiolate). This reaction is advantageously carried out between 0° C. and 110° C., preferably between 20° C. and 40° C., in the presence of a catalytic amount of a phosphine (such as triphenylphosphine) and in an aprotic solvent, such as tetrahydrofuran (THF), dioxane, toluene or dichloromethane.
Particular Embodiment for Step 2a.
The acrylate of structure A can subsequently react with a 6-halogeno-1-aminoisoquinoline, such as a 6-bromo-1-aminoisoquinoline (which is substituted by a R2 group as defined above), the primary amine functional group of which is protected by a group Pg2, for example a triphenylmethyl (trityl) group, in the presence of a transition metal complex (for example, palladium acetate in combination with a tetraalkylammonium halide hydrate such as tetraethylammonium chloride hydrate), in an aprotic solvent, such as THF, dioxane, N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA), at a temperature of between 20 and 150° C., to give the compound of 3-(1-aminoisoquinolin-6-yl)-2-pyrrolidinoacrylate type of structure B.
Particular Embodiment for Step 3a.
The derivative B can subsequently be reduced to give the derivative of structure C using hydrogen at a pressure of 1 to 5 bar, at a temperature of between 20 and 100° C., in a protic solvent, such as methanol, ethanol or isopropanol, optionally in combination with an aprotic solvent, such as THF, ethyl acetate or DMF. This hydrogenation can be catalysed by a complex of a transition metal, such as rhodium or ruthenium, with a chiral phosphine, such as 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) or 1,2-bis(2,5-dimethylphospholano)benzene (DUPHOS), such as (R,R)-(DUPHOS)Rh(COD). The derivative of 3-(1-aminoisoquinolin-6-yl)-2-pyrrolidinopropanoate type of structure C thus obtained has the 2R or 2S configuration according to the enantiomer of the chiral phosphine used.
Particular Embodiment for Step 4a.
The derivative D is subsequently obtained by deprotection of Pg1, by techniques known to a person skilled in the art, of the primary amine functional protective group Pg, present on the pyrrolidinone ring. During this stage, the protective group of the primary amine Pg2 of the isoquinoline can either remain present (X=Pg2) or be also removed (X=H). A salt of the compound D may also optionally be formed in acidic medium.
For example, in the case where Pg1 represents a tert-butyl carbamate, the amine of the derivative C is released using an acid in an anhydrous medium, such as hydrogen chloride in dioxane or trifluoroacetic acid in dichloromethane. The amine carried by the isoquinolinyl group will also be released to give the compound D in which Pg2 becomes a hydrogen atom (X=H). Furthermore, in the case where Pg1 represents a benzyl carbamate, the amine of the derivative C can be selectively released by catalytic hydrogenolysis in ethanol or methanol, in the presence of palladium-on-charcoal, in which case the protective group Pg2 on the amine of the isoquinoline will remain present in the derivative D (X=Pg2).
Particular Embodiment for Step 5a.
The derivative D can subsequently be reacted in an aprotic solvent, such as dichloromethane, THF or DMF, with a sulphonyl halide of formula R3—SO2Hal, where R3 is as defined above in connection with the formula (I) and Hal represent a halogen atom, preferably Cl. The reaction is carried out in the presence of a base, in particular a tertiary amine, such as triethylamine or N,N-diisopropylethylamine, at a temperature of between −10° C. and 50° C., to result in the sulphonamide of structure E.
Particular Embodiment for Optional Step 6a.
Optionally, the sulphonamide E is subsequently deprotected to result in the compound of formula (I) in accordance with the present invention.
During this stage, the removal of the protective group Pg2 and optionally the cleavage of the O—R1 bond (R1 being not H) are carried out using organic chemistry techniques well known to a person skilled in the art.
For example, when R1 is methyl and Pg2 is trityl, the Pg2 group is removed by reaction with trifluoroacetic acid in dichloromethane or else with anhydrous hydrogen chloride in dioxane and then the R1 group can optionally be removed by hydrolysis of the ester using sodium hydroxide in an appropriate solvent or mixture of solvents, such as THF, ethanol and water.
The salt of the compound of formula (I) may be obtained by the addition of the corresponding acid.
Particular Embodiments for Optional Step 7a.
According to a first embodiment, compounds of formula (I) in which R1 represents an alkyl, a cycloalkyl or a cycloalkylalkyl may be obtained by transesterification of a compound of formula (I) as obtained in step 6a with the corresponding R1—OH (alcohol, cycloalkylalcohol or cycloalkylalkylalcohol), in the presence of an alkoxide of metal such as titanium (IV) isopropoxide. This reaction is generally conducted at a temperature comprised between 20° C. and the reflux temperature of the reaction mixture.
According to a second embodiment, compounds of formula (I) in which R1 represents a H atom may be obtained from a compound of formula (I) where R1 is C1-C6 alkyl, cycloalkyl or cycloalkylalkyl as obtained in step 6a by hydrolysis of R1.
More particularly, the hydrolysis may be carried out in aqueous acidic media such as 1M hydrochloric acid at a temperature comprised between 20° C. and the reflux temperature of the reaction mixture, such as 80° C. to provide the corresponding carboxylic acid where R1 is Hydrogen.
According to a third embodiment, compounds of formula (I) in which R1 represents a Rb—O—Ra—, Rd-O—C(O)—O-Rc-, or Rf—C(O)—O—Re— group as defined above may be obtained from a compound of formula (I) where R1 is C1-C6 alkyl, cycloalkyl or cycloalkylalkyl as obtained in step 6a by hydrolysis of R1 in order to obtain the corresponding compound of formula (I) with R1 being H, this hydrolysis being optionally followed by an esterification with the corresponding R1-Hal where Hal is a halogen atom such as Cl.
More particularly, the hydrolysis may be carried out in aqueous acidic media such as 1M hydrochloric acid at a temperature comprised between 20° C. and the reflux temperature of the reaction mixture, such as 80° C. to provide the corresponding carboxylic acid where R1 is Hydrogen. The resulting carboxylic acid is then esterified by reacting the acid with the corresponding compound Rb—O—Ra-Hal, Rd-O—C(O)—O-Rc-Hal, or Rf—C(O)—O—Re-Hal where Hal represents a halogen atom, such as Cl. The compound Rb—O—Ra-Hal may be formed in situ in the presence of Rb—O—Ra—OH with thionyl halogenide, such as thionyl chloride. This esterification reaction may be carried out in the presence of an organic base such as diethylisopropylamine or an inorganic base such as potassium or cesium carbonate at room temperature. Additionally, potassium iodide could be added in the reaction medium for halogen exchange and to improve the alkylation process leading to esters of formula (I) where R1 represents Rb—O—Ra—, Rd-O—C(O)—O-Rc-, or Rf—C(O)—O—Re—, Ra, Rb, Rc, Rd, Re and Rf having the above definitions.
In Scheme 1, the starting compounds and the reactants, when their method of preparation is not described or cited above or below (for instance in the examples), are commercially available or are described in the literature or else can be prepared according to methods which are described therein or which are known to a person skilled in the art.
According to another of its aspects, another subject-matter of the invention is the compounds of formula A, B, C, D and E. These compounds are of use as intermediates in the synthesis of the compounds of formula (I).
where R1 is H or an alkyl, a cycloalkyl or a cycloalkylalkyl-, R2, R2′ and R3 are defined above, Pg, is an amino protective group, X is H or Pg2 and Pg2 is an amino protective group.